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Dronedarone (an investigational anti-arrhythmic) reduces hospitalizations and cardiovascular death but not total mortality in selected patients with atrial fibrillation (the ATHENA trial)

Although it was not the pre-specified primary endpoint, the most impressive effect of dronedarone in this placebo-controlled study was a 9.8% per year reduction in "any hospitalization due to any cardiovascular event or death from any cause." The actual rates were 54% with dronedarone and 71.7% with placebo (p < 0.001) over a mean follow-up of 21 months (1.75 years). Since death from any cause was not different (5% with dronedarone and 6% with placebo), one might conclude that the number needed to treat (NNT) for one year to prevent one hospitalization due to a cardiovascular event is about 10 patients.

The impact of anticoagulation was not evaluated in this trial but the study is being highlighted here because of the prevalence of atrial fibrillation (AF) as an indication for anticoagulation. This highly publicized trial has been heralded as the first large trial to show a reduction in mortality with treatment of atrial fibrillation - but does it? Closer scrutiny reveals that cardiovascular deaths - but not total mortality - were reduced significantly. The greatest numerical impact was on reducing hospitalizations for cardiovascular events (as discussed above); but issues of patient selection may be important to keep in mind. Let's look at what the trial found - and did not find.

Although the difference in primary the endpoint ("first hospitalization due to cardiovascular events or death") was impressive (31.9% dronedarone vs. 39.4% placebo), the percent of deaths included in that composite endpoint were no different (2.6% dronedarone vs 2.5% placebo). Further, death from any cause also was not significantly different (5% dronedarone vs 6% placebo). And the perceived clinical impact of the reported differences was somewhat reduced in that these differences occurred over a mean follow-up of 21 months (1.75 years). That is, these results were not expressed as percent per patient-year.

The good news, however, is that there was a significant reduction in cardiovascular deaths (2.7% dronedarone vs 3.9% placebo, p=0.03 - but that would be an absolute difference of 0.7% per year). This difference in cardiovascular deaths was due in large part to a reduction in arrhythmia deaths, which also was significant (1.1% dronedarone vs 2.1% placebo, p=0.01; absolute difference of 0.6% per year.). Still, in relative terms, these differences are significant but not too clinically impressive. The number of patients needed to treat (NNT) for one year to prevent one such event would be about 167. It is important to realize, however, that the primary endpoint was the FIRST hospitalization; the results improved when "any" hospitalization for a cardiovascular event was counted (as discussed above).

There are some limitations of this study that one should keep in mind when applying the results to individual patients. Patients with permanent AF were excluded as were patients with New York Heart Association Class IV heart failure (HF). Also, because the mortality rate was low during the initial part of the study, the inclusion criteria were modified during the study in order to enroll patients at higher risks. Thirty percent of patients in each arm discontinued the therapy with more patients receiving dronedarone stopping therapy because of adverse effects (12.7% dronedarone vs 8.1% placebo) and more patients on placebo stopping therapy for "other" reasons (14.4% placebo vs 9.4% dronedarone) with the difference being due to more patients on placebo stopping study therapy in order to start other anti-arrhythmic therapy or recurrent AF. One case of torsades de points was reported in the dronedarone group. The mean follow-up of 21 months may be inadequate to assess any potential concerns regarding pulmonary or other potential delayed toxicity.

The findings of this trial should be considered in light of an earlier trial that reported an increased mortality with dronedarone in patients with NYHA class IV heart failure.2 In that trial, the increased mortality was due mainly to increased HF deaths. It has been postulated that dronedarone either may have a detrimental effect in severe HF or the deaths reported in that trial may have been due to interruption of other therapies (such as ACE inhibitors) in response to the now recognized effect of dronedarone to increase the serum creatinine (but apparently without altering glomerula filtration).

Based on ATHENA, dronedarone in some patients with AF offers a substantial reduction in hospitalizations for cardiovascular events and a reduction in arrhythmia-induced or cardiovascular deaths; but not all-cause mortality.